PROJECT SUMMARY/ABSTRACT Sickle cell disease (SCD) is one of the most common monogenic diseases affecting over 300,000 births worldwide and 1 in 400 of African descent. In the last few decades, SCD has evolved from a life-threatening disease of childhood to a chronic disease in adults. With improved survival and reduced disease-related morbidity, reproductive health is emerging as a priority in SCD care. However, appropriate fertility counseling and treatment recommendations are limited by our lack of understanding of the impact of SCD and disease- modifying therapies on reproduction. There is an urgent need to evaluate the fertility and to optimize fertility preservation options in women affected by SCD. The objectives of this proposal are to evaluate how SCD affects ovarian reserve and female fertility, and to determine what the best timing and methods to preserve fertility are in these women. The central hypothesis is that SCD leads to accelerated ovarian aging through chronic tissue hypoxia and inflammation, which adversely affects the fertility of women with SCD. Utilizing our complementary expertise and an existing adult SCD clinical research program, we propose the following studies to achieve our objectives: Aim 1. Measure ovarian reserve in adult women with SCD and follow longitudinally over two years. Aim 2. Establish optimal fertility preservation protocol in a pilot cohort of women with SCD and optimize the management of any adverse events that occur during their assisted reproductive treatments. Aim 3. Assess ovarian aging acceleration and inflammation in the ovarian granulosa cells obtained from women with SCD, as compared with age-matched non-SCD controls. These studies will the first to systematically evaluate the impact of SCD on ovarian aging and female fertility from both clinical and molecular levels. This work will significantly improve our ability to counsel women with SCD on their risks of infertility and how these risks are modified by age and disease severity. This grant will lay important groundwork for a more comprehensive study on ovarian pathophysiology in adolescent females with SCD, with the goal of optimizing fertility preservation prior to onset of end-organ damage in this younger population. The preliminary data obtained from this study will also serve as the basis for establishing a national registry to surveil fertility preservation approaches and long-term outcomes in women with SCD seeking fertility evaluation and treatments. These investigations will increase our understanding of how SCD impacts female fertility and serve the unmet reproductive health needs of all women with SCD.